Patients with chronic lymphocytic leukemia (CLL) and high-risk genetic mutations typically have poor response to ibrutinib monotherapy, but adding ublituximab, a novel anti-CD20 monoclonal antibody, to their treatment could improve response rates, according to results of the phase III GENUINE study presented at the 2017 ASCO Annual Meeting.

“Despite the introduction of ibrutinib and other targeted agents, patients with CLL continue to relapse and complete remissions are rare,” Jeff P. Sharman, MD, director of research at Willamette Valley Cancer Institute and Research Center in Springfield, Oregon, and lead author of the study, said during his presentation of the results. “The GENUINE study met its primary endpoint, demonstrating that ublituximab in combination with ibrutinib yields a superior overall response rate to ibrutinib alone in [this patient population].”

Dr. Sharman and co-authors enrolled adult patients with relapsed/refractory CLL who had at least one high-risk genetic feature (del17p, del11q, or TP53 mutation) and an Eastern Cooperative Oncology Group score of 0 to 2. Patients were excluded from the trial if they received any anti-cancer therapy 21 days prior to enrollment or autologous hematopoietic cell transplantation 3 months prior to enrollment. There was no limit on the number of prior therapies patients received, but patients were excluded if they were previously treated with ibrutinib or other Bruton tyrosine kinase inhibitors.

A total of 126 patients (median age = 67 years; range = 43-87 years) were randomized 1:1 to receive ibrutinib 420 mg once-daily, with or without ublituximab 900 mg (administered intravenously on days 1, 8, and 15 of cycle 1, day 1 of cycles 2-6, and every third day thereafter). At the time of data cut-off (February 15, 2017), 117 patients had been treated: 59 in the ublituximab plus ibrutinib arm, and 58 in the ibrutinib-alone arm.

Patients had received a median of three prior therapies (range = 1-8). “High-risk cytogenetics were relatively balanced,” the authors noted, “with approximately 50 percent of patients having del17p.”

The ublituximab combination was well tolerated, Dr. Sharman reported. “With the exception of infusion-related reactions, ublituximab did not alter the safety profile of ibrutinib monotherapy.”

Infusion reactions were the most common adverse event (AE) in the ublituximab arm (all-grade = 44%; grade 3/4 = 5%), and rates of other AEs were similar between both study arms:

diarrhea: 43% vs. 40% (ublituximab + ibrutinib vs. ibrutinib alone)

fatigue: 27% vs. 33%

nausea: 22% vs. 21%

headache: 20% vs. 28%

arthralgia: 19% vs. 17%

anemia: 14% vs. 17%

Rates of neutropenia were comparable between the groups, as well (3% vs. 2%).

Among the 53 patients in each arm who were evaluable for minimal residual disease (MRD), rates of MRD negativity were also higher in the ublituximab cohort (19% vs. 2%; p<0.001).

“The addition of ublituximab to ibrutinib demonstrated a superior response rate compared to ibrutinib alone without additional clinically significant toxicity,” the authors concluded. Though they reported observing advantages in progression-free survival and radiographic complete response rate in the ublitixumab plus ibrutinib arm, these results are still being confirmed. Dr. Sharman also noted that the median time to response was shorter in the combination arm than the ibrutinib-alone arm (1.97 months vs. 3.8 months), but this analysis is ongoing.

The study’s findings are limited by the small patient population, and the trial was not powered to determine secondary endpoints (including rates of complete response, progression-free survival, time to response, and safety). Future trials will need to compare ublituximab combinations with other combinations, including the anti-CD20 monoclonal antibody rituximab.